Cytotoxic effects of topotecan combined with various active G2/M-phase anticancer drugs in human tumor-derived cell lines

Topotecan (TPT) is a DNA-Topoisomerase I poison that exhibits antitumor act ivity. TPT, like other DNA-damaging agents, arrests or delays cell cycle pr ogression during S- and G2-phase in a wide variety of tumor-derived cell li nes. Particularly, the G2-arrest gives time for the cell to repair its DNA lesions prior to starting a new cell cycle. Based on these observations, we assessed the interaction between TPT and G2/M-active agents in p53-mutated cell lines of diverse origin in order to achieve cell toxicity. Two short- term sequential schedules were administered (TPT --> G2/M-active drug at th e interval of greatest TPT-induced G2/M-phase cell arrest, and G2/M-active drug --> TPT), in three human tumor-derived cell lines with proven sensitiv ity to the following drugs: Bleomycin in HEp-2 (squamous larynx carcinoma); Docetaxel in SKBr-3 (breast adenocarcinoma); Etoposide in NCI-H23 (non-sma ll-cell lung cancer). Our results show that: 1) Sequential TPT --> G2/M-act ive drugs are synergistic when administration overlapped the maximum percen tage of TPT-induced G2/M-phase cell arrest interval in all three mutated p5 3 cell lines; 2) the reverse sequential schedule (G2/M-active drug --> TPT) was antagonistic, and being only additive for Etoposide --> TPT associatio n. In conclusion, our findings further support the potential cytotoxic role of TPT in combination with other active drugs when the correct schedule of administration is applied. In addition, they provide a rationale for new a pplications in clinical trials using short-term sequential TPT --> G2/M-act ive drugs.